Expression of β-catenin in hepatocellular carcinoma

AIM: The β-catenin has been recognized as a critical member of the Wnt signaling pathway and plays an important role in the generation/differentiation of many tissues. Inappropriate activation of this pathway has been implicated in carcinogenesis. The mechanism underlying the development as well as its prognosis of hepatocellular carcinoma (HCC) has remained unclear. The purpose of this study is to analyze the expression of β-catenin in HCC in relation to histological grades and viral hepatitis backgrounds. METHODS: Thirty-two sections were selected at random from autopsy and surgical cases of HCC. Immuohistologically, the location and positivity of β-catenin expression in HCC was examined. RESULTS: Normal hepatocytes did not express β-catenin. In 78% of HCC β-catenin was expressed at the membrane of the cells, with or without cytoplasmic and/or nuclear expression. The tumor cells with well- and moderately-differentiated grades expressed frequently at the membrane and cytoplasm compared with poorly-differentiated type. Nuclear expression of β-catenin was prone to occur in the tumor cells of poorly-differentiated grade. There were 15% of hepatitis C virus (HCV) backgrounds with nuclear expression. In contrast, there was 38% with nuclear expression in hepatitis B virus (HBV) backgrounds. In nonBnonC hepatitis, no case expressed nuclear β-catenin. CONCLUSION: The β-catenin expression in HCC cells was heterogenous among types of hepatitis viral infection. Wnt signaling pathway might be deeply involved in less-differentiated HCC and HBV background.     

Human thiopurine S-methyltransferase pharmacogenetics: variant allozyme misfolding and aggresome formation

Thiopurine S-methyltransferase (TPMT) catalyzes the S-methylation of thiopurine drugs. TPMT genetic polymorphisms represent a striking example of the potential clinical value of pharmacogenetics. Subjects homozygous for TPMT*3A, the most common variant allele for low activity, an allele that encodes a protein with two changes in amino acid sequence, are at greatly increased risk for life-threatening toxicity when treated with standard doses of thiopurines. These subjects have virtually undetectable levels of TPMT protein. In this study, we tested the hypothesis that TPMT*3A might result in protein misfolding and aggregation. We observed that TPMT*3A forms aggresomes in cultured cells and that it aggregates in vitro, functional mechanisms not previously described in pharmacogenetics. Furthermore, there was a correlation among TPMT half-life values in rabbit reticulocyte lysate, aggresome formation in COS-1 cells, and protein aggregation in vitro for the three variant allozymes encoded by alleles that include the two TPMT*3A single-nucleotide polymorphisms. These observations were compatible with a common structural explanation for all of these effects, a conclusion supported by size-exclusion chromatography and CD spectroscopy. The results of these experiments provide insight into a unique pharmacogenetic mechanism by which common polymorphisms affect TPMT protein function and, as a result, therapeutic response to thiopurine drugs.     

Health-related quality-of-life assessment in patients with cutaneous T-cell lymphoma

OBJECTIVE: To measure and evaluate the health-related quality of life (HRQOL) in patients with cutaneous T-cell lymphoma (CTCL), a visible cutaneous malignancy that may have a profound effect on patients' lives. DESIGN: Monocenter, cross-sectional study. SETTING: The Skin Oncology Program, Department of Dermatology, and the Photopheresis Unit of Boston Medical Center. PATIENTS: A total of 22 adult patients with confirmed CTCL. MAIN OUTCOME MEASURES: (1) Evaluation of general oncologic and skin disease-specific HRQOL using, respectively, the Functional Assessment of Cancer Therapy-General (FACT-G) and Skindex-29 profiles; (2) assessment of HRQOL association with disease stage (early stage, IA-IIA; late stage, IIB-IVB). RESULTS: Patients with more advanced CTCL stages reported more effects on general health (FACT-G), particularly in the physical, emotional, and functional domains (P < .05). Patients with early-stage CTCL reported better skin-specific HRQOL overall (Skindex-29; P = .002) and for each specific domain than did patients with late-stage disease. The Skindex-29 scales had high internal consistency, and the confirmatory factor structure was similar to that of previous studies. CONCLUSIONS: The HRQOL of patients with CTCL can be evaluated using the Skindex-29 and FACT-G instruments. Patients with more advanced stages of CTCL had lower HRQOL scores.     

Augmentation of tendon-bone healing by the use of calcium-phosphate cement

The healing of a hamstring graft to bone is the weak link in the reconstruction of a cruciate ligament using this donor material. We therefore investigated the augmentation of healing at the tendon-bone interface using calcium-phosphate cement (CPC). We performed semitendinosus autograft reconstructions of the anterior cruciate ligament on both knees of 22 New Zealand white rabbits. The interface between the grafted tendon and the bone tunnel for one knee was filled with CPC. Six rabbits were killed at the end of the first and second post-operative weeks in order to evaluate the biomechanical changes. Two rabbits were then killed sequentially at the end of weeks 1, 3, 6, 12 and 24 after operation and tissue removed for serial histological observation. Histological examination showed that the use of CPC produced early, diffuse and massive bone ingrowth. By contrast, in the non-CPC group of rabbits only a thin layer of new bone was seen. Mechanical pull-out testing at one week showed that the mean maximal tensile strength was 6.505 +/- 1.333 N for the CPC group and 2.048 +/- 0.950 N for the non-CPC group. At two weeks the values were 11.491 +/- 2.865 N and 5.452 +/- 3.955 N, respectively. Our findings indicate that CPC is a potentially promising material in clinical practice as regards its ability to reinforce the fixation of the tendon attachment to bone and to augment the overall effectiveness of tendon healing to bone.     

Sleep-disordered breathing is not associated with the presence of retinal microvascular abnormalities: the Sleep Heart Health Study

STUDY OBJECTIVE: Sleep apnea and milder forms of sleep-disordered breathing (SDB) have been associated with overt clinical cardiovascular disease, but it is unknown whether SDB is associated with arterial microvascular pathology. We examined the relation between SDB and retinal microvascular abnormalities. DESIGN: Cross-sectional study. PARTICIPANTS: Subjects were 2,927 men and women, aged 51 to 97 years, who participated in the Sleep Heart Health Study and had retinal photographs taken within approximately 3 years of overnight, unattended, at-home polysomnography. MEASUREMENTS AND RESULTS: A respiratory disturbance index (RDI), calculated as the average number of apneas and hypopneas per hour of sleep, was used as an indicator of SDB in analysis. The overall prevalence of retinopathy was slightly higher in people with higher RDI values (5.4%, 4.9%, 8.6%, and 7.6%, respectively, in increasing quartiles of RDI), but after adjustment for age, body-mass index, hypertension, diabetes, and other factors, the presence of retinopathy was not associated with SDB. With the possible exceptions of microaneurysms and generalized arteriolar narrowing, as measured by lower arteriole-to-venule ratio, specific retinal abnormalities were not associated consistently with the RDI. Relative to the first quartile of RDI, the adjusted odds ratios (95% confidence interval) for the presence of microaneurysm in the second, third, and fourth quartiles of RDI were 1.05 (0.44-2.55), 1.97 (0.89-4.37), and 1.79 (0.78-4.10), respectively. An increase of RDI from 0 to 10 was associated with a predicted decrease in arteriole-to-venule ratio of 0.01. Results were similar when analyses were conducted in normotensive and nondiabetic persons separately. CONCLUSIONS: These data do not demonstrate a notable relation between SDB and retinal abnormalities. However, since this is the first investigation of a link between retinopathy and SDB, similar studies should be conducted in other population samples to demonstrate either consistency or inconsistency of our findings across studies.     

Medically eligible women who do not use HAART: the importance of abuse, drug use, and race

OBJECTIVES: We investigated the prevalence and characteristics of HIV-positive women who do not report highly active antiretroviral therapy (HAART) use. METHODS: We analyzed HAART use among 1165 HIV-positive participants in the Women's Interagency HIV Study. RESULTS: Between October 1, 2000, and March 31, 2001, 254 women with clinical indications for HAART reported not using it, 635 reported HAART use, and 276 had no clinical indications. In multivariate analysis, using crack/cocaine/heroin and a history of abuse decreased the likelihood of using HAART, whereas being White increased it. CONCLUSIONS: One of 4 women for whom HAART was indicated reported not using HAART. Childhood sexual abuse prevention, more intensive abuse treatment, and continuing drug treatment may enhance HIV disease treatment of women.     

Prevention of macrophage adhesion molecule-1 (Mac-1)-dependent neutrophil firm adhesion by taxifolin through impairment of protein kinase-dependent NADPH oxidase activation and antagonism of G protein-mediated calcium influx

Taxifolin has been reported to down-regulate the expression of intercellular adhesion molecule-1 (ICAM-1), a receptor-mediating firm adhesion with beta2 integrin (e.g., Mac-1) expressed on leukocytes. To evaluate whether taxifolin could modulate Mac-1-dependent firm adhesion by neutrophils, and the possible mechanism(s) underlying its anti-inflammatory action, its effects on N-formyl-methionyl-leucyl-phenylalanine (fMLP) or phorbol-12-myristate-13-acetate (PMA)-activated peripheral human neutrophils were studied. Pretreatment with taxifolin (1-100 microM) concentration-dependently diminished fMLP- or (PMA)-induced Mac-1-dependent firm adhesion and upexpression of surface Mac-1. Mobilisation of intracellular calcium and production of reactive oxygen species (ROS) signal the upexpression of Mac-1 and firm adhesion by neutrophils. Taxifolin impeded the calcium influx induced by fMLP (a receptor-mediated activator) or AlF(4)(-) (a G protein-mediated activator). Taxifolin also effectively inhibited the fMLP- or PMA-induced ROS production with 50% inhibitory concentration (IC(50)) less than 10microM, possibly through impairing the activation of NADPH oxidase, a major ROS-generating enzyme in neutrophils, by restricting the activation of p38 mitogen-activated protein kinase (p38 MAPK) and protein kinase C (PKC). In conclusion, we propose that impairment of ROS production by NADPH oxidase through interfering with p38 MAPK- and/or PKC-dependent signals, and antagonism of G protein-mediated calcium influx may account for the inhibition of Mac-1-dependent neutrophil firm adhesion that confers taxifolin the anti-inflammatory activity.